[C]-fused bicyclic proline derivatives and their use for treating arthritic conditions

Abstract

This invention relates to a compound which is [c]-fused bicyclic proline derivative, or a pharmaceutically acceptable salt thereof; a pharmaceutical composition comprising the compound or the salt thereof, and methods of treating diseases, including, but not limited to, methods of preventing or inhibiting joint cartilage damage and preventing or treating diseases characterized by joint cartilage damage, joint inflammation, or joint pain. The [c]-fused bicyclic proline derivatives are compounds of Formula I as described above. Diseases characterized by joint cartilage damage or joint pain include, for example, osteoarthritis and rheumatoid arthritis. Rheumatoid arthritis is also characterized by joint inflammation. This invention also relates to methods of synthesizing and preparing the [c]-fused bicyclic proline derivatives, or a pharmaceutically acceptable salt thereof.

1 . A compound of Formula I  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,  
         wherein:  
         Z is selected from COOH, C(O)N(H)R 9 , and Z 1 ;  
         Z 1  is selected from:  
         
           
             
             
                 
                 
             
           
         
         Each Y 4 , Y 5 , Y 6 , and Y 7  is C(R 10 )R 10w ; or  
         One of Y 4 , Y 5 , Y 6 , and Y 7  is selected from O, S, S(O), S(O) 2 , and NR 5 , and the other three of Y 4 , Y 5  Y 6 , and Y 7  are each C(R 10 )R 10w ; or  
         Two nonadjacent Y 4 , Y 5 , Y 6  and Y 7  are independently selected from O, S, S(O), S(O) 2 , and NR 5 , and the other two of Y 4 , Y 5 , Y 6 , and Y 7  are each C(R 10 )R 10w ;  
         Each R 2 , R 3 , R 3w , R 3a , R 7a , R 10 , and R 10w  is independently selected from: H, HO, H 2 N, H 2 NS(O) 2 -(G) m , HS, Halo, CN, CF 3 , FC(H) 2 O, F 2 C(H)O, CF 3 O, and  
         a group, which may be unsubstituted or substituted, independently selected from:  
         C 1 -C 6  alkyl-(G) m -, C 2 -C 6  alkenyl-(G) m -, C 2 -C 6  alkynyl-(G) m -, 2- to 6-membered heteroalkyl-(G) m -, 2- to 6-membered heteroalkenyl-(G) m -, C 3 -C 7  cycloalkyl-(G) m -, C 3 -C 7  cycloalkenyl-(G) m -, C 7 -C 10  bicycloalkyl-(G) m -, 3- to 7-membered heterocycloalkyl-(G) m -, 7- to 10-membered heterobicycloalkyl-(G) m -, Phenyl-(G) m -, Naphthyl-(G) m -, 5- and 6-membered heteroaryl-(G) m -, 8- to 10-membered heterobiaryl-(G) m -, and  
         any of the above R 2 , R 3 , R 3w , R 3a , R 7a , R 10 , and R 10w  groups each independently substituted on carbon or nitrogen atoms with from 1 to 6 substituents R X ;  
         wherein R 3  and R 3w , and any geminal pair of R 10  and R 10w , and any two R X  substituents geminally substituted on a carbon atom in substituted R 2 , R 3 , R 3w , R 3a , R 7a , R 10  and R 10w  groups further may independently be taken together with a carbon atom to which they are both bonded to form the group C(═O);  
         R 1  is HO or a group that may be unsubstituted or substituted, independently selected from:  
         C 1 -C 6  alkyl-(T) m -, C 2 -C 6  alkenyl-(T) m -, C 2 -C 6  alkynyl-(T) m -, 2- to 6-membered heteroalkyl-(T) m -, 2- to 6-membered heteroalkenyl-(T) m —, C 3 -C 7  cycloalkyl-(T) m -, C 3 -C 7  cycloalkenyl-(T) m -, C 7 -C 10  bicycloalkyl-(T) m -, 3- to 7-membered heterocycloalkyl-(T) m -, 7-to 10-membered heterobicycloalkyl-(T) m -, Phenyl-(T) m -, Naphthyl-(T) m -, 5- and 6-membered heteroaryl-(T) m -, 8- to 10-membered heterobiaryl-(T) m -, and  
         any of the above R 1  groups independently substituted on a carbon or nitrogen atom, with from 1 to 6 substituents R X ;  
         R 1  may further be H when: (i) at least one of R 2 , R 3 , R 3w , R 3a , R 7a , R 10 , and R 10w  is not H, or (ii) Z is C(O)N(H)R 9  wherein R 9  is as defined above wherein m is 1 and L is S(O) 2 , or (iv) Z is Z 1 ;  
         Each R 5  and R 9  is independently H, HO, or a group, which may be unsubstituted or substituted, independently selected from: C 1 -C 6  alkyl-(L) m -, C 2 -C 6  alkenyl-(L) m -, C 2 -C 6  alkynyl-(L) m -, 2- to 6-membered heteroalkyl-(L) m -, 2- to 6-membered heteroalkenyl-(L) m -, C 3 -C 7  cycloalkyl-(L) m -, C 3 -C 7  cycloalkenyl-(L) m , C 7 -C 10  bicycloalkyl-(L) m -, 3- to 7-membered heterocycloalkyl-(L) m -, 7- to 10-membered heterobicycloalkyl-(L) m -, Phenyl-(L) m -, Naphthyl-(L) m -, 5- and 6-membered heteroaryl-(L) m -, 8- to 10-membered heterobiaryl-(L) m -, and  
         any of the above R 5  and R 9  groups independently substituted, on carbon or nitrogen atoms, with from 1 to 6 substituents R X ;  
         wherein any 2 groups each selected from R 5 , R 10 , and R 10w  that are bonded to contiguous carbon or nitrogen atoms in Formula I may be taken together with the contiguous atoms in Formula I to which they are bonded to form C═C or C═N;  
         wherein any 2 groups selected from R 1 , R 2 , R 3 , R 3w , R 3a , R 5 , R 7a , R 10 , and R 10w  that are bonded to contiguous carbon or nitrogen atoms in Formula I may be taken together to form (i) a diradical selected from CH 2  and CH 2 CH 2 CH 2 , (ii) a 3-membered diradical selected from:  
         
           
             
             
                 
                 
             
           
         
         (iii) a 4-membered diradical selected from:  
         
           
             
             
                 
                 
             
           
         
         wherein any two groups R 3  and R 3w , and R 10  and R 10w , that are geminally bonded to a single carbon atom in Formula I may be taken together to form a 4-membered diradical as defined above or a 5-membered diradical selected from:  
         
           
             
             
                 
                 
             
           
         
         wherein any 2 groups selected from R 1 , R 2 , R 3 , R 3w , R 3a , R 5 , R 7a , R 10 , and R 10w  that are bonded to noncontiguous carbon or nitrogen atoms in Formula I may be taken together to form (i) a CH 2 CH 2  diradical or (ii) —O— diradical;  
         X is O, S, S(O), S(O) 2 , or N—R;  
         X 1  is O or N—R;  
         Each G is independently selected from C(═O), S(O), S(O) 2 , OC(O), N(R 4 )C(O), (C 1 -C 8  alkylenyl) m , (2- to 8-membered heteroalkylenyl) m , and (C 1 -C 8  alkylenyl) m  and (2- to 8-membered heteroalkylenyl) m  independently substituted on carbon or nitrogen atoms with from 1 to 4 substituents R X ;  
         Each T is independently selected from S(O), S(O) 2 , N(R 4 )C(O), (C 1 -C 8  alkylenyl) m , (2- to 8-membered heteroalkylenyl) m , and (C 1 -C 8  alkylenyl) m  and (2- to 8-membered heteroalkylenyl) m  independently substituted on carbon or nitrogen atoms with from 1 to 4 substituents R X ;  
         Each L is independently selected from O, N(R 4 ), S(O), S(O) 2 , C(═O), C(O)O, OC(O), C(O)N(R 4 ), N(R 4 )C(O), OC(O)N(R 4 ), N(R 4 )C(O)o, N(R 4 )C(O)N(R 4w ), (C 1 -C 8  alkylenyl) m , (2- to 8-membered heteroalkylenyl) m , and (C 1 -C 8  alkylenyl) m  and (2- to 8-membered heteroalkylenyl) m  independently substituted on carbon or nitrogen atoms with from 1 to 4 substituents R X ;  
         Each R, R 4 , and R 4w  is independently H or C 1 -C 6  alkyl, which C 1 -C 6  alkyl may be unsubstituted or substituted with from 1 to 3 substituents R X ;  
         Each R X  is independently selected from: HO, H 2 N, H 2 NS(O) 2 , CN, CF 3 , FCH 2 O, F 2 C(H)O, CF 3 O, O 2 N, C 1 -C 6  alkyl-(Q) m -, 2- to 6-membered heteroalkyl-(Q) m -, C 3 -C 7  cycloalkyl-(Q) m -, 3- to 7-membered heterocycloalkyl-(Q) m -, Phenyl-(Q) m , and 5-membered heteroaryl-(Q) m ,  
         wherein phenyl and 5-membered heteroaryl-(Q) m  each is unsubstituted or independently substituted with from 1 to 3 substituents selected from halo, HO, HOC(O), CH 3 OC(O), CH 3 C(O), H 2 N, CF 3 , CN, and C 1 -C 6  alkyl;  
         wherein each R X  substituent on a carbon atom may further be independently selected from: HS, (C 1 -C 6  alkyl)-S, halo, and HO 2 C; and  
         Each Q independently is O, N(R 6 ), S(O), S(O) 2 , C(═O), C(O)O, OC(O), C(O)N(R 6 ), N(R 6 )C(O), OC(O)N(R 6 ), N(R 6 )C(O)O, or N(R 6 )C(O)N(R 6 );  
         Each R 6  and R 6w  independently is H or unsubstituted C 1 -C 6  alkyl;  
         Each m independently is an integer of 0 or 1; and  
         Each n independently is an integer of from 0 to 2.  
       
     
     
         2 . The compound according to  claim 1  of Formula II  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,  
         wherein R 1  is HO or a group that may be unsubstituted or substituted, independently selected from:  
         C 1 -C 6  alkyl-(T) m -, C 2 -C 6  alkenyl-(T) m -, C 2 -C 6  alkynyl-(T) m -, 2- to 6-membered heteroalkyl-(T) m -, 2- to 6-membered heteroalkenyl-(T) m —, C 3 -C 7  cycloalkyl-(T) m -, C 3 -C 7  cycloalkenyl-(T) m -, C 7 -C 10  bicycloalkyl-(T) m -, 3- to 7-membered heterocycloalkyl-(T) m -, 7-to 10-membered heterobicycloalkyl-(T) m -, Phenyl-(T) m -, Naphthyl-(T) m -, 5- and 6-membered heteroaryl-(T) m -, 8- to 10-membered heterobiaryl-(T) m -, and  
         any of the above R 1  groups independently substituted on a carbon or nitrogen atom, with from 1 to 6 substituents R X ;  
         Each T is independently selected from S(O), S(O) 2 , N(R 4 )C(O), (C 1 -C 8  alkylenyl) m , (2- to 8-membered heteroalkylenyl) m , and (C 1 -C 8  alkylenyl) m  and (2- to 8-membered heteroalkylenyl) m  independently substituted on carbon or nitrogen atoms with from 1 to 4 substituents R X ;  
         Each R 4  is independently H or C 1 -C 6  alkyl, which C 1 -C 6  alkyl may be unsubstituted or substituted with from 1 to 3 substituents R X ;  
         Each R X  is independently selected from: HO, H 2 N, H 2 NS(O) 2 , CN, CF 3 , FCH 2 O, F 2 C(H)O, CF 3 O, O 2 N, C 1 -C 6  alkyl-(Q) m -, 2- to 6-membered heteroalkyl-(Q) m -, C 3 -C 7  cycloalkyl-(Q) m -, 3- to 7-membered heterocycloalkyl-(Q) m -, Phenyl-(Q) m , and 5-membered heteroaryl-(Q) m ,  
         wherein phenyl and 5-membered heteroaryl-(Q) m  each is unsubstituted or independently substituted with from 1 to 3 substituents selected from halo, HO, HOC(O), CH 3 OC(O), CH 3 C(O), H 2 N, CF 3 , CN, and C 1 -C 6  alkyl;  
         wherein each R X  substituent on a carbon atom may further be independently selected from: HS, (C 1 -C 6  alkyl)-S, halo, and HO 2 C; and  
         Each Q independently is O, N(R 6 ), S(O), S(O) 2 , C(═O), C(O)O, OC(O), C(O)N(R 6 ), N(R 6 )C(O), OC(O)N(R 6 ), N(R 6 )C(O)O, or N(R 6 )C(O)N(R 6w );  
         Each R 6  and R 6w  independently is H or unsubstituted C 1 -C 6  alkyl; and  
         Each m independently is an integer of 0 or 1.  
       
     
     
         3 . The compound according to  claim 2 , wherein R 1  is unsubstituted or substituted C 1 -C 6  alkyl-(L) m .  
     
     
         4 . The compound according to  claim 1 , selected from: 
 1,2-dimethyl-octahydro-isoindole-1-carboxylic acid hydrochloride;    1-methyl-octahydro-isoindole-1-carboxylic acid hydrochloride;    5,6-Dimethoxy-octahydro-isoindole-1-carboxylic acid;    cis-2,3,3a,4,7,7a-Hexahydro-1H-isoindole-1-carboxylic acid hydrochloride;    diastereomer 1 of 6-chloro-2,2-dimethyl-octahydro-[1,3]dioxolo[4,5-f]isoindole-5-carboxylic acid; and    diastereomer 2 of 6-chloro-2,2-dimethyl-octahydro-[1,3]dioxolo[4,5-f]isoindole-5-carboxylic acid; or    a pharmaceutically acceptable salt thereof.    
     
     
         5 . The compound according to  claim 1  selected from: 
 3-aza-6,6-oxabicyclo[4.3.0]nonane-2-arboxylic acid;    10-oxa-4-aza-tricyclo[5.2.1.0 2,6 ]decane-3-carboxylic acid;    4-methyl aza-tricyclo[5.2.2.0 2,6 ]undecane-3-carboxylic acid hydrochloride; and    4-aza-tricyclo[5.2.2.0 2,6 ]undecane-3-carboxylic acid hydrochloride; or    a pharmaceutically acceptable salt thereof.    
     
     
         6 . The compound according to  claim 1 , selected from: 
 3-aza-6,6-difluorobicyclo[3.3.0]octane-2-carboxylic acid;    3-aza-6-fluorobicyclo[3.3.0]octane-2-carboxylic acid;    3-aza-6-n-butoxybicyclo[3.3.0]octane-2-carboxylic acid;    3-aza-6-hydroxybicyclo[3.3.0]octane-2-carboxylic acid hydrochloride;    3-azaoxobicyclo[3.3.0]octane-2-carboxylic acid hydrochloride;    octahydro-pyrrolo[2,1-a]isoindole-9b-carboxylic acid hydrochloride; or    a pharmaceutically acceptable salt thereof.    
     
     
         7 . The compound according to  claim 1 , selected from: 
 7a-benzyl-octahydro-isoindole-1-carboxylic acid hydrochloride;    7a-methyl-octahydro-isoindole-1-carboxylic acid;    3,3-dimethyloctahydro-isoindole-1-carboxylic acid hydrochloride;    3-(octahydro-isoindol-1-yl)-4H-[1,2,4]oxadiazol-5-one; and    3-(2-methyl-octahydro-isoindol-1-yl) 4 H-[1,2,4]oxadiazol-5-one; or    a pharmaceutically acceptable salt thereof.    
     
     
         8 . A pharmaceutical composition, comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.  
     
     
         9 . A pharmaceutical composition, comprising a compound according to  claim 2 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.  
     
     
         10 . A method of treating joint cartilage damage, osteoarthritis, rheumatoid arthritis, or joint inflammation, or alleviating joint pain, in a mammal suffering from joint cartilage damage, osteoarthritis, rheumatoid arthritis, joint inflammation, or joint pain, respectively, comprising administering to the mammal a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof.  
     
     
         11 . A method of treating joint cartilage damage, osteoarthritis, rheumatoid arthritis, or joint inflammation, or alleviating joint pain, in a mammal suffering from joint cartilage damage, osteoarthritis, rheumatoid arthritis, joint inflammation, or joint pain, respectively, comprising administering to the mammal a compound according to  claim 2 , or a pharmaceutically acceptable salt thereof.